The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins

Ning Li; Maryam Yousefi; Angela Nakauka-Ddamba; Fan Li; Lee Vandivier; Kimberly Parada; Dong-Hun Woo; Shan Wang; Ammar S Naqvi; Shilpa Rao; John Tobias; Ryan J Cedeno; Gerard Minuesa; Katz Y; Trevor S Barlowe; Alexander Valvezan; Sheila Shankar; Raquel P Deering; Peter S Klein; Shane T Jensen; Michael G Kharas; Brian D Gregory; Zhengquan Yu; Christopher J Lengner

doi:10.1016/j.celrep.2015.11.022

The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins

Cell Rep. 2015 Dec 22;13(11):2440-2455. doi: 10.1016/j.celrep.2015.11.022. Epub 2015 Dec 8.

Authors

Ning Li¹, Maryam Yousefi², Angela Nakauka-Ddamba³, Fan Li⁴, Lee Vandivier⁵, Kimberly Parada³, Dong-Hun Woo³, Shan Wang¹, Ammar S Naqvi⁶, Shilpa Rao⁷, John Tobias⁷, Ryan J Cedeno², Gerard Minuesa⁸, Katz Y⁹, Trevor S Barlowe⁸, Alexander Valvezan¹⁰, Sheila Shankar³, Raquel P Deering⁹, Peter S Klein¹¹, Shane T Jensen¹², Michael G Kharas⁸, Brian D Gregory⁴, Zhengquan Yu¹³, Christopher J Lengner¹⁴

Affiliations

¹ State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ PENN Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁰ Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China. Electronic address: zyu@cau.edu.cn.
¹⁴ Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lengner@vet.upenn.edu.

Abstract

Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Transformation, Neoplastic
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Disease Models, Animal
Female
Genes, Reporter
HCT116 Cells
Humans
Intestinal Mucosa / metabolism
Intestinal Mucosa / pathology
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Knockout
Mice, Nude
Mice, Transgenic
Multiprotein Complexes / metabolism
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
RNA Interference
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
TOR Serine-Threonine Kinases / metabolism
Transplantation, Heterologous
beta Catenin / antagonists & inhibitors
beta Catenin / genetics
beta Catenin / metabolism

Substances

Msi1h protein, mouse
Msi2h protein, mouse
Multiprotein Complexes
Nerve Tissue Proteins
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
RNA-Binding Proteins
beta Catenin
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase

Abstract

Publication types

MeSH terms

Substances

Grants and funding